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Vol. 13, No. 2, pp. 188-201, January 15, 1999
1 Department of Microbiology and Molecular Genetics,
University of Medicine and Dentistry of New Jersey (UMDNJ), New Jersey
Medical School, Newark, New Jersey 07103 USA;
2 Department of
Microbiology, Duke University Medical Center, Durham,
North Carolina 27710 USA
We have developed an in vitro mRNA stability system using HeLa cell
cytoplasmic S100 extracts and exogenous polyadenylated RNA substrates
that reproduces regulated aspects of mRNA decay. The addition of cold
poly(A) competitor RNA activated both a sequence-specific deadenylase
activity in the extracts as well as a potent, ATP-dependent ribonucleolytic activity. The rates of both deadenylation and degradation were up-regulated by the presence of a variety of AU-rich
elements in the body of substrate RNAs. Competition analyses demonstrated that trans-acting factors were required for RNA
destabilization by AU-rich elements. The ~30-kD ELAV protein HuR
specifically bound to RNAs containing an AU-rich element derived from
the TNF-
mRNA in the in vitro system. Interaction of HuR with
AU-rich elements, however, was not associated with RNA destabilization.
Interestingly, recombinant ELAV proteins specifically stabilized
deadenylated intermediates generated from the turnover of AU-rich
element-containing substrate RNAs. These data suggest that mammalian
ELAV proteins play a role in regulating mRNA stability by influencing
the access of degradative enzymes to RNA substrates.
[Key Words: Deadenylation; mRNA degradation; poly(A); ELAV proteins; mRNA stability]
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